Methods of treatment of asthma and COPD

ABSTRACT

Described herein are methods of administering the non-steroidal anti-inflammatory drug norketotifen, an isomer, an isomeric mixture, a prodrug, or a pharmaceutically acceptable salt thereof for the treatment of a respiratory disorders such as COPD and asthma to human patient in need of such treatment, without exposing said patient to adverse immune-suppressive effects. Methods include treating acute and potentially life-threatening exacerbations of COPD and asthma with norketotifen.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. application Ser. No.16/751,539 filed Jan. 24, 2020, which claims priority to U.S.Provisional Application 62/809,212 filed on Feb. 22, 2019, which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The embodiments disclosed herein relate to methods for the treatment ofasthma and COPD with norketotifen, specifically RS-norketotifen.

BACKGROUND

Pulmonary disorders such as asthma and chronic obstructive pulmonarydisorder (COPD) are significant pulmonary problems in humans. Asthma isan inflammatory disease of the lungs that affects all age groups ofpatients and is characterized by recurrent attacks (exacerbations) ofbreathlessness and wheezing. The global prevalence of asthma is about330 million patients with an annual asthma-related death rate of about500,000 patients. Asthma-related deaths occur in connection withexacerbations of the disease. COPD is an umbrella term that is used tocover certain inflammatory lung diseases such as “emphysema” and“chronic bronchitis”. The estimated global prevalence of COPD is similarto asthma with about 330 million patients worldwide. However, the annualCOPD-related death rate has been estimated at 3.2 million patients.COPD-related deaths occur in connection with exacerbations of thedisease.

In humans, both asthma and COPD are currently treated with inhaledanti-inflammatory corticosteroids, inhaled bronchodilators, andcombinations thereof. The steroids are usually administered directlyinto the lungs by use of various types of inhalers. Currently, no potentinflammatory drugs are available that are free from the adverseimmune-suppressive effects. Even the anti-inflammatory monoclonalantibodies potently express adverse suppression of the immune system.

What is needed for the treatment of pulmonary inflammatory conditionsare non-steroidal long-acting oral anti-inflammatory drugs that do nothave the adverse effects of steroids.

SUMMARY

In one aspect, a method of treating a human patient in need of treatmentfor asthma or COPD comprises administering orally or by oral inhalationan anti-inflammatory corticosteroid medication; discontinuing thecorticosteroid medication; and administering orally or by oralinhalation to the human patient a therapeutically effective amount ofthe anti-inflammatory compound norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereof,wherein the norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof reduces the immune-suppressioncaused by the anti-inflammatory corticosteroid medication.

A method of treating a human patient in need of treatment for an acuteexacerbation of asthma or an acute exacerbation of COPD comprises orallyor by oral inhalation administering to the human patient in need thereofa therapeutically effective amount of norketotifen, an isomer, anisomeric mixture, a prodrug, or a pharmaceutically acceptable saltthereof; wherein the therapeutically effective amount of norketotifen,an isomer, an isomeric mixture, a prodrug, or a pharmaceuticallyacceptable salt thereof provides a concentration of norketotifen in thelungs of the patient that is greater than or equal to the MIC ofnorketotifen for Haemophilus influenza, Streptococcus pneumoniae,Moraxella catarrhalis, Staphylococcus aureus, Staphylococcusintermedius, Klebsiella pneumoniae, a Trichophyton sp., or a combinationthereof.

A method of treating acute exacerbations of asthma or acuteexacerbations of COPD in a human patient in need of such treatmentcomprises orally or by oral inhalation administering to the humanpatient an original therapeutically effective maintenance dosage ofnorketotifen, an isomer, an isomeric mixture, a prodrug, or apharmaceutically acceptable salt thereof for the treatment of chronicinflammation associated with asthma or COPD; identifying a symptomindicative of onset of acute exacerbation of asthma or acuteexacerbation of COPD in the human patient, wherein the symptom is anincrease in severity and/or frequency of cough, an increase in breathingdifficulty, change in color and/or amount of sputum, increased fatigue,reduced oxygen levels, increased carbon dioxide levels, decreased FEV-1,fever, expression of pulmonary microbial infections or a combinationthereof, wherein the symptom is novel or acutely increased in severityin the patient; administering to the patient exhibiting the symptom atleast a double dosage of the original therapeutically effectivemaintenance dosage of the norketotifen, isomer, isomeric mixture,prodrug, or pharmaceutically acceptable salt thereof; continuing the atleast double dose of the original therapeutically effective maintenancedosage of norketotifen, isomer, prodrug, or pharmaceutically acceptablesalt thereof until the acute exacerbation of asthma or acuteexacerbation of COPD in the human patient resolves, or continuing the atleast double dose of the original therapeutically effective amount ofnorketotifen, isomer, prodrug, or pharmaceutically acceptable saltthereof for the duration of treatment; and optionally after resolutionof the acute exacerbation of asthma or the acute exacerbation of COPD,orally or by oral inhalation administering to the human patient, arevised maintenance dose of norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereof forthe continued treatment of asthma or COPD.

In yet another aspect, a method of treating COPD exacerbations in ahuman patient suffering from COPD comprises identifying an acute onsetof a symptom of COPD in the human patient, wherein the symptom comprisescough, increased mucus, wheezing, shortness of breath, frequentrespiratory infections, fatigue, or a combination thereof; identifyingan episode when the symptom worsens more than day-to-day variation for aperiod of time that persist for several days or up to weeks; and inresponse to the exacerbation, orally or by oral inhalation administeringto the human patient a therapeutically effective amount of norketotifen,an isomer, an isomeric mixture, a prodrug, or a pharmaceuticallyacceptable salt thereof.

In another aspect, a method of treating a patient suffering from arespiratory disorder, COPD or asthma, comprising orally or by oralinhalation administering to the human patient a therapeuticallyeffective amount of norketotifen, an isomer, an isomeric mixture, aprodrug, or a pharmaceutically acceptable salt thereof, while avoidinginflicting said patients with adverse corticosteroidal side effects.

DETAILED DESCRIPTION

Described herein are studies showing that norketotifen is even morepotent than the well-known steroid prednisone/prednisolone in thetreatment of respiratory disorders, but importantly, norketotifen is thefirst potent anti-inflammatory pulmonary drug to be free from theadverse immune-suppressive effects of the steroids. Thus, norketotifencan be used as a potent anti-inflammatory drug without adverseimmune-suppressant activities.

It has now also been found that norketotifen expresses anti-microbialeffects against several types of bacteria, fungi and mold that commonlyinfect the lungs of patients suffering from pulmonary disorders such asasthma and COPD and also of patients suffering from inflammatory airwaysdisorders. Prior to the present disclosure, it had not been shown thatorally or oral-pulmonary administered norketotifen has antimicrobialpulmonary effects. As shown herein, inhaled norketotifen is undoubtedlyreaching and exceeding the pulmonary concentrations needed forantimicrobial efficacy.

The methods described herein relate to methods of treating asthma andCOPD by administering norketotifen, an isomer, a prodrug, or apharmaceutically acceptable salt thereof, orally, by oral inhalation orby nasal inhalation. In an aspect, the compound is RS-norketotifen.Prior to the present disclosure, the respiratory therapeutic efficacy ofnorketotifen administered orally and by inhalation and had not beenconfirmed.

Asthma is a common long-term inflammatory disease of the airways. It ischaracterized by variable and recurring symptoms, reversible airflowobstruction, and easily triggered bronchospasms. Symptoms includeepisodes of wheezing, coughing, chest tightness, and shortness ofbreath. Asthma can be classified as atopic and non-atopic. The symptomsof asthma can sometimes be prevented by avoiding triggers, such asallergens and irritants and by use of inhaled anti-inflammatory drugs,such as acute anti-inflammatory drugs or long-acting drugs that preventsthe inflammatory symptoms of asthma.

Chronic obstructive pulmonary disease (COPD) is characterized byobstructive inflammation causing inhibited airflow and poor breathing.The older term “chronic bronchitis” is used to define a productive andrecurrent cough, while the term “emphysema” is still used and refers tothe existence of air in the pulmonary tissues. In contrast to asthma,the airflow reduction does not improve much with the use ofbronchodilators in COPD patients. Tobacco smoking is the primary riskfactor for development of COPD.

COPD is characterized by an increase in inflammatory cytokines, such asIL-1, IL-6, IL-8, IL-12, IFN-gamma, IL-18, and TNF-alpha, which arereleased from pro-inflammatory cells (such as mast cells, basophils,macrophages, eosinophils). Symptoms of COPD include shortness of breath,especially during physical activities, wheezing, chest tightness,chronic cough, frequent respiratory infections, and combinationsthereof. COPD patients often complain of lack of energy.

In humans, both asthma and COPD are currently treated withanti-inflammatory corticosteroids, inhaled bronchodilators and mostoften, combinations thereof. To decrease systemic adverse effects and toshorten the onset time of the medication, corticosteroids areadministered directly to the lungs by inhalation devices, such as forexample hydrofluoroalkane (HFA) inhalers, metered dose inhalers (MDI),dry powder inhalers (DPI) and nebulizers. Adverse effects from use ofinhalation devices are few although thrush (an oral yeast infections)and hoarseness occur. Thrush is treated with oral antifungal medicationsand hoarseness is usually treated by rinsing the mouth (gargling).

An advantage of using norketotifen for the treatment of asthma and COPDis that the risk for adverse systemic immune-suppression is decreased.Unlike corticosteroids which must be dosed at the lowest dose possible,norketotifen may be used in higher oral doses than possible forsteroids.

In addition, the use of norketotifen will avoid adverse systemic effectsof corticosteroids such as adrenal gland atrophy; cataracts; facial hairgrowth; glaucoma; growth retardation in children; headache; high bloodpressure; increased blood glucose and loss of diabetes control; loss ofpotassium; menstrual irregularity; muscle weakness; obesity;osteoporosis; puffiness of the face (moon face); slow wound healing;sodium and fluid retention causing edema and weight gain; thinning andeasy bruising of the skin; ulcers in the stomach and duodenum; andothers.

In the treatment of respiratory disorders, norketotifen does not causeadverse immune suppression which is contrary to the steroids. Thus,norketotifen may be used in higher doses and higher concentrations andfor longer periods of time than possible for steroids.

The methods described herein relate to the treatment of asthma and COPDin human patients, by oral dosing, by oral inhalation, or by nasalinhalation of norketotifen or an isomer or a prodrug or apharmaceutically acceptable salt thereof. In an aspect, the compound isRS-norketotifen or a salt thereof. Prior to the present disclosure, therespiratory/pulmonary therapeutic efficacy of orally administerednorketotifen, for example, had not been reported. Since norketotifen isa low-toxicity drug, the oral doses of norketotifen can be high duringthe initial loading phase and reduced during a maintenance phase.

Of particular note, norketotifen differs from the glucocorticoids, sincenorketotifen, after oral administration, is rapidly absorbed and issurprisingly preferentially distributed to the lungs, where theconcentration of RS-norketotifen can reach concentrations that may be100 times higher than the plasma concentration. This finding (see Table3) is particularly surprising since it is contrary to current teachingthat pulmonary drug concentrations cannot exceed the plasmaconcentration.

In addition to oral administration, the RS-norketotifen can beadministered to the nasal passages using nasal drops or nasal sprays orby oral inhalation devices such as for example metered dose inhalers,dry powder inhalers, HFA inhalers and nebulizers using doses needed andas often as needed by the patient and selected by his/her physician orcaregiver.

As used herein, norketotifen refers to norketotifen, an isomer, aprodrug, or a pharmaceutically acceptable salt thereof. RS-norketotifenrefers to racemic norketotifen. In an aspect, the compound isRS-norketotifen hydrogen fumarate.

Norketotifen is an achiral molecule, but has two atropisomers,S-norketotifen and R-norketotifen, as has previously been described byAberg et al. in U.S. Pat. Nos. 7,226,934 and 7,557,128.

As explained in U.S. Pat. Nos. 7,226,934 and 7,557,128, norketotifen hadsignificant sedative effects when studied in an art-accepted mouse modelof sedation, and further, the sedative effects were attributed to theR-isomer. It was thus proposed that only the S-isomer could beadministered without sedative side effects. It has later been found thatorally administered RS-norketotifen is free from sedative side effectsin dogs (U.S. Pat. No. 8,557,846) and in humans (U.S. Pat. Nos.9,138,431 and 9,345,697). Therefore, unlike for ketotifen, nodose-limiting sedative adverse effects are expected for norketotifen,even after high oral doses of norketotifen

As used herein, a single isomer has an optical purity of 90% or more;preferably 98% or better. Also as used herein, an isomeric mixture hasan optical purity of 90/10 to 10/90 for the S-isomer/the R-isomer. Aracemate as used herein has an optical purity of between 50/50 and 60/40for one isomer/the other isomer.

Norketotifen can be made using methods known in the art, as described inU.S. Pat. No. 3,682,930, the disclosure of which is hereby incorporatedby reference for its teaching of the synthesis of norketotifen.

Prodrugs of norketotifen include N-substituted hydroxyalkyl orcarboxyalkyloxyalkyl analogs thereof. Such molecules are described inU.S. Pat. No. 6,297,683. Prodrugs of norketotifen include molecules ofthe formula:

wherein R is hydroxy-C₂-C₆ alkyl or carboxy-C₁-C₆alkoxy-C₁-C₆alkyl.Additional prodrugs include substituents at the 8-position, the10-position and/or in the 12 to 17 positions and/or inclusion ofsubstituents on various positions on the piperidine ring.

As used herein, the terms “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to norketotifen salts,which have been prepared from pharmaceutically acceptable non-toxicacids. Exemplary pharmaceutically acceptable acid as for the compound ofthe present invention include acetic, benzenesulfonic (besylate),benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic,phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric, and thelike. The hydrochloride salt and the hydrogen fumarate salt areparticularly preferred.

Oral administration of norketotifen to treat pulmonary disorders, forapproximately 1 week or less (loading dose) can then be followed by alower maintenance dose, which at the discretion of the caregiver can becontinued for 1 week, 10 days, weeks, months or years or rest of life(ROL). This is particularly important because conditions such as asthmaand COPD are most often chronic conditions, requiring treatment forweeks, months, or years. Thus, norketotifen will preferably andinitially be administered once or twice daily for up to one week, whichis the loading dose, followed by a lower, maintenance dose ofnorketotifen once or twice daily or less frequently than once daily forone week, several weeks, one month, several months, one year or severalyears or ROL.

More specifically, in a study in dogs, (Table 2), once daily orallyadministered norketotifen was found to accumulate in the lungs, and theconcentration in the lungs was 70 times higher than in the plasma. In asimilar study in rats, the pulmonary concentration of norketotifen was100 times higher in lungs than in plasma (Table 3). It is quitesurprising that the concentration of norketotifen in the lungs is higherthan the plasma drug concentration because it is generally believed inthe art that pulmonary concentrations of drugs are not higher than thecorresponding plasma-drug concentrations due to the lack of knowntransporters between the blood and the lungs.

A method of treating a human patient in need of treatment for asthma orCOPD comprises administering orally or by oral inhalation ananti-inflammatory corticosteroid medication; discontinuing thecorticosteroid medication; and administering orally or by oralinhalation to the human patient a therapeutically effective amount ofthe anti-inflammatory compound norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereof,wherein the norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof reduces the immune-suppressioncaused by the anti-inflammatory corticosteroid medication.

In this aspect, the human patient has been treated with acorticosteroid, which currently is the standard of care for asthma orCOPD. During the course of treatment, the corticosteroid isdiscontinued, and then norketotifen, an isomer, an isomeric mixture, aprodrug, or a pharmaceutically acceptable salt thereof is administeredto the patient, preferably as a long-term replacement for thecorticosteroid treatment.

As used herein, discontinuing can be an abrupt stop with a substantiallyimmediate transition to norketotifen therapy. Alternatively,discontinuing can be a gradual discontinuation, over days or even weeks,wherein the dosing of the corticosteroid is gradually reduced, such asskipping doses or administering smaller doses. Replacement therapy withnorketotifen can begin during the gradual discontinuation of thecorticosteroid, for example such that the amount or frequency of dosingof the norketotifen is gradually increased during the discontinuation ofthe steroid. Alternatively, replacement therapy with the norketotifen isnot started until after the last dose of the corticosteroid isadministered to the patient. However the corticosteroid and norketotifenare administered, it is important that the patient receive continuedanti-inflammatory drug treatment.

In an aspect, wherein the norketotifen, isomer, isomeric mixture,prodrug, or pharmaceutically acceptable salt thereof provides improvedbreathing and life-saving therapy to the human patient, wherein thehuman patient is a critically sick patient. Such therapy is particularlyimportant for critically sick patients particularly in view of the highmortality rate for asthma and in particular for COPD patients.

In this context it is important that corticosteroids do not work well inCOPD patients and in patients with severe asthma. The lack oftherapeutic activity is corticosteroid resistance. High doses ofcorticosteroids may reduce the exacerbations by 20-25% in patients withsevere disease and this is the clinical indication for their use. Exceptfor norketotifen, effective anti-inflammatory medications forCOPD-patients are not known. Also, it is difficult and currently notpossible to construct a monoclonal antibody with widespread use fordiseases like COPD, which are not caused by a single gene defect, butare polygenic. Due to the lack of effective medications for COPD, morethan 300 million patients are without effective medication and 3.2million COPD-patients die yearly from COPD. The following cytokines areamong the multitude of cytokines involved in COPD exacerbations: IL-1,IL-6, IL-8, and TNFα; all are inhibited by norketotifen (Table 6). Thesimultaneous release of these cytokines in COPD exacerbations representa pulmonary Cytokine Storm.

In another aspect, and based on current studies, the anti-inflammatorydrug norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof will prolong life compared tono treatment or to continued treatment with the corticosteroid.

In another aspect, a method of treating a human patient in need oftreatment for an acute and severe exacerbation of asthma or an acuteexacerbation of COPD comprises orally or by oral inhalationadministering to the human patient in need thereof a therapeuticallyeffective amount of norketotifen, an isomer, an isomeric mixture, aprodrug, or a pharmaceutically acceptable salt thereof; wherein thetherapeutically effective amount of norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereofprovides a concentration of norketotifen in the lungs that is greaterthan or equal to the MIC for Haemophilus influenza, Streptococcuspneumoniae, Moraxella catarrhalis, or a combination thereof. Moraxellacatarrhalis causes 2 to 4 million exacerbation of COPD annually in theUSA.

An acute exacerbation of severe asthma or an acute exacerbation of COPDis a flare-up of asthma or COPD, generally caused by a cytokine stormcharacterized by simultaneous release of high concentrations of numerouspro-inflammatory cytokines, resulting in worsening of the pulmonaryinflammation and an increase in the intensity of symptoms. Acute COPDexacerbations are most often cause by pulmonary bacterial infectionswhich result in simultaneous release of additional cytokines. Often, thepatient will have an infection-related fever in addition the COPDsymptoms.

A severe exacerbation of COPD generally results in hospitalization andpatients often require mechanical respiratory support. Patients withsevere acute exacerbations COPD have a significant in-hospital mortalityrate which in one study was a one-year mortality of 59 percent. Withoutbeing held to theory, it is believed that mortality is caused bymicrobial infections which in turn cause a release of multiplecytokines, giving rise to severe pulmonary inflammation and severepulmonary edema, often necessitating the use of respirators or similardevices. Patients suffering from severe COPD exacerbations feels worsewhen lying down and they often prefer sitting in a chair when sleeping.These patient generally have severe pulmonary infections, oftenexpressed as colds, flu or pneumonia. The severe pulmonary infectionsand the severe inflammation cause lung damage that can be permanent.

In certain aspects, the norketotifen, isomer, isomeric mixture, prodrug,or pharmaceutically acceptable salt thereof provides life-saving therapyto asthma patients with severe exacerbations. In other aspects, theacute exacerbation of asthma or acute exacerbation of COPD in the humanpatient are not seldom severe and life-threatening.

In another aspect, the MIC for Haemophilus influenza was found to beabout 0.25 mg/ml, the MIC for Streptococcus pneumoniae was 0.5 mg/ml,and the MIC for Moraxella catarrhalis was 0.25 mg/ml (see Table 9).

In certain aspects, the norketotifen, isomer, isomeric mixture, prodrug,or pharmaceutically acceptable salt thereof relieves one or moresymptoms of asthma or COPD selected from phlegm, stabbing chest pain,shortness of breath, difficult breathing, wheezing, yellow or greencolored mucus, fever, chills, throat pain, sinus drainage andcongestion.

In certain aspects, the method further comprises diagnosing arespiratory infection associated with the acute exacerbation of asthmaand particularly of COPD. Methods for diagnosing respiratory infectionsinclude medical imaging, spirometry, pulse oximetry, mucus culture,throat swab, complete blood count, blood culture, or a combination ofthe foregoing.

In another aspect, a method of treating acute exacerbations of asthma oracute exacerbations of COPD in a human patient in need of such treatmentcomprises orally or by oral inhalation administering to the humanpatient an original therapeutically effective maintenance dosage ofnorketotifen, an isomer, an isomeric mixture, a prodrug, or apharmaceutically acceptable salt thereof for the treatment of chronicinflammation associated with asthma or COPD; identifying a symptomindicative of onset of acute exacerbation of asthma or acuteexacerbation of COPD in the human patient, wherein the symptom is anincrease in severity and/or frequency of cough, an increase in breathingdifficulty, change in color and/or amount of sputum, increased fatigue,reduced oxygen levels, increased carbon dioxide levels, decreased FEV-1,fever, expression of pulmonary microbial infections or a combinationthereof, wherein the symptom is novel or increased in severity in thepatient; administering to the patient exhibiting the symptom at least adouble dosage of the original therapeutically effective maintenancedosage of the norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof; continuing the at least doubledose of the original therapeutically effective maintenance dosage ofnorketotifen, isomer, prodrug, or pharmaceutically acceptable saltthereof until the acute exacerbation of asthma or acute exacerbation ofCOPD in a human patient resolves, or continuing the at least double doseof the original therapeutically effective amount of norketotifen,isomer, prodrug, or pharmaceutically acceptable salt thereof for theduration of the exacerbation treatment; and optionally after resolutionof the acute exacerbation of asthma or the acute exacerbation of COPD,orally or by oral inhalation administering to the human patient, arevised maintenance dose of norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereof forthe continued treatment of asthma or COPD.

In an aspect, the acute exacerbation of asthma or acute exacerbation ofCOPD is associated with a bacterial or fungal infection of the lungs inthe human patient. The bacterial or fungal infection may be caused bybacteria, such as Haemophilus influenza, Streptococcus pneumoniae,Moraxella catarrhalis, or fungi, such as Trichophyton sp., orcombinations thereof. Pulmonary infections may start with Enterovirusinfections that are co-expressed by bacterial (such as H influenza, Spneumoniae and/or M catarrhalis) and/or fungal (such as Trichophyton)infections. The pulmonary bacterial and fungal infections trigger thedegranulation of pro-inflammatory cells and the release large numbers ofvarious cytokines from pro-inflammatory cells.

In one aspect, the at least a double dose of the originaltherapeutically effective amount of norketotifen, isomer, isomericmixture, prodrug, or pharmaceutically acceptable salt thereof can beaccompanied by administering antimicrobial drugs. Antimicrobial drugsfor COPD and asthma patients will be as recommended by the hospital orthe medical professionals and are often drugs like ofloxacin or relatedfluoroquinolones. In general, prescriptions of antibiotics to patientswith obstructive pulmonary diseases often follow the localantibiotic-sparing rules in different countries and may includecephalosporines, macrolides, tetracyclins or quinolones. Examples oforal antifungal drugs are voriconazole and amphoterizine B.

In an aspect, the acute exacerbation of asthma or acute exacerbation ofCOPD in the human patient is severe or life-threatening.

In another aspect, a method of treating COPD exacerbations in a humanpatient suffering from COPD comprises identifying an acute onset of asymptoms of COPD in the human patient, wherein the symptom comprisesongoing cough, increased mucus, wheezing, shortness of breath, frequentrespiratory infections, fatigue, or a combination thereof; identifyingan episode when the symptom worsens more than day-to-day variation for aperiod of time that persist for several days or up to weeks; and inresponse to the exacerbation, orally or by oral inhalation administeringto the human patient a therapeutically effective amount of norketotifen,an isomer, an isomeric mixture, a prodrug, or a pharmaceuticallyacceptable salt thereof.

In the foregoing method, the norketotifen eliminates the microorganismsthat stimulate the release of cytokines from pro-inflammatory cells,further inhibiting the degranulation of pro-inflammatory granulocytes toreduce or prevent the release of cytokines associated with COPD, therebyterminating the exacerbation and make possible the return to amaintenance dosing of norketotifen to the patient.

In an aspect, the norketotifen is administered in the form of a tablet,a capsule, or a syrup. In another aspect, the method further comprisesfurther administering a second therapeutically active agent,specifically a long-acting muscarinic antagonist (a LAMA), a long-actingbeta receptor agonist (a LABA) or a combination thereof.

In an aspect, the oral daily loading dosage is from about 0.5 mg toabout 50 mg once or more times daily of the norketotifen, isomer,prodrug or pharmaceutically acceptable salt thereof, calculated asnorketotifen free base and administered one or more times daily. Forexample, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mg and up to 50 mg onceor more times daily of norketotifen, isomer, prodrug or pharmaceuticallyacceptable salt thereof can be administered as the loading dosage.

In an aspect, the oral daily maintenance dosage is maintenance dosage isfrom about 0.5 mg to about 20 mg of norketotifen, isomer, prodrug orpharmaceutically acceptable salt thereof, calculated as norketotifenfree base, and administered one or more times daily. For example, about0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19or 20 mg and up to 50 mg once or more timed daily of norketotifen,isomer, prodrug or pharmaceutically acceptable salt thereof can beadministered as the maintenance dosage.

In an aspect, the respiratory disorder for treatment with oralnorketotifen is a pulmonary disorder in addition to asthma and COPD suchas Chronic Respiratory Disease (CRD), Restrictive Lung Disease and Upperor Lower Respiratory tract infections.

In another aspect, the respiratory disorder for treatment with oralnorketotifen is an airways disorder such as non-allergic rhinitis,vasomotor rhinitis, non-allergic rhinitis with eosinophil syndrome,chronic rhinitis, senile rhinitis, sinusitis, laryngitis, acutebronchitis, acute bronchitis with cough, chronic bronchitis, ornasopharyngitis.

In an aspect, the oral administration of norketotifen has avoidedadverse effects associated with chronic administration of other potentanti-inflammatory drugs, such as corticosteroids, calcineurininhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors andanti-inflammatory monoclonal antibodies, all of which cause adversesuppression of the immune system either systemically or locally at thesite of application

In addition to its anti-inflammatory properties, norketotifen hasantimicrobial activity and is expected to inhibit the pulmonary growthof microorganisms such as fungi, specifically molds, and bacteriaincluding Malassezia sp, Trichophyton sp., Haemophilus influenza,Streptococcus intermedius, Moraxella catarrhalis, Candida albicans, andStaphylococcus sp. Staphylococcus sp. bacterial infections of the lungsare not uncommon in human patients and a clinical study demonstratedmortality of 32 percent of these patients, despite antibiotic treatmentof the pulmonary infections. Pulmonary infections with Candida sp arewell-known and pulmonary Malassezia sp. infections are also well-known.Thus, the respiratory disorders treatable with norketotifen inaccordance with the dosing regimens described herein can includebacterial and fungal pulmonary infections.

In another aspect, disclosed herein is a method of treating asthma orCOPD in a human patient in need of such treatment, comprisingadministering by oral inhalation a therapeutically effective amount ofnorketotifen, an isomer, a prodrug or a pharmaceutically acceptable saltthereof to the patient suffering from asthma or COPD, wherein the lungsof said patient are affected by a respiratory bacterial, fungal or moldinfection. In an aspect, the therapeutically effective amount of thenorketotifen, isomer, prodrug or pharmaceutically acceptable saltthereof provides a pulmonary concentration that is equal to or greaterthan the minimum inhibitory concentration (MIC) value for the bacteria,fungus or mold. Table 6 provides exemplary MIC values.

Usually, a free pulmonary concentration of norketotifen that is equal toor greater than the minimum inhibitory concentration (MIC) value for thebacteria, fungi or mold may not be achieved by oral, e.g., systemic,administration. Only oral inhalation of norketotifen can provideconcentrations of norketotifen that are high enough to kill microbes inthe lungs. Administering norketotifen by oral inhalation (for example bya dry powder inhaler) can save the lives of COPD patients by eliminationof the microbes that cause life-threatening pulmonary infections. Inaddition, norketotifen prevents inflammations that accompany theinfections.

In another aspect, the therapeutically effective amount of thenorketotifen, isomer, isomeric mixtures prodrug or pharmaceuticallyacceptable salt thereof reduces or eliminates a symptom of therespiratory bacterial, fungal or mold infection in the patient.Exemplary symptoms of respiratory infection include cough with phlegm,stabbing chest pain, shortness of breath, difficult breathing, wheezing,yellow or green colored mucus, fever, chills, throat pain, sinusdrainage or congestion, headache, and combinations thereof.

Pulmonary infections can be diagnosed by listening for abnormal soundsin the lungs when a patient is breathing. In addition, X-ray and CTscans can be helpful to diagnose bacterial pneumonia in the lowerrespiratory tract. The respiratory infection can be diagnosed by medicalimaging (chest x-ray or CT scan), spirometry, pulse oximetry, mucusculture, throat swab, complete blood count, blood culture, or acombination of the foregoing.

In an aspect, administration by inhalation is performed using a drypowder inhaler, a metered dose inhaler, an HFA inhaler, a nebulizer, ora digital inhaler.

In an aspect, the therapeutically effective amount of inhalednorketotifen, or an isomer, or a prodrug or a pharmaceuticallyacceptable salt thereof, for providing therapeutically effectivepulmonary concentration will depend on the disease of the patient(asthma or COPD) and the severity of concomitant pulmonary microbialinfections. While any suitable inhaler may be used, patients sufferingfrom severe pulmonary infections may prefer a dry powder inhaler thatcan deliver from 10 μg and up to 500 μg of micronized norketotifen peractuation. The inhaled dose of norketotifen in severely sick patientsmay consist of up to six or more daily actuations from a high-capacityDPI device.

Because norketotifen is not a penicillin and because norketotifenaccumulates in the lungs, it is expected to be effective in thetreatment of infections with penicillin-resistant bacteria in the lungs.Exemplary bacteria include methicillin-resistant Staphylococcus aureus(MRSA), vancomycin-resistant Enterococcus (VRE), drug-resistantStreptococcus pneumoniae (DRSP) and multi-drug resistant Mycobacteriumtuberculosis (MDR TB). It is understandable by those skilled in the artthat norketotifen can be combined with other anti-microbial drugs.

In addition to inhibiting the growth of bacteria, norketotifen has beenfound to inhibit the growth of fungi, particularly the mold Trichophytonsp. such as Trichophyton rubrum, which can be found in the lungs ofsubjects with asthma and COPD. Thus, in an aspect, norketotifen can beadministered by an inhaler to subjects in need of treatment forTrichophyton asthma or Trichophyton COPD. In an aspect, the subjectdemonstrates fungal sensitization demonstrated by an increase in serumIgE specific to Trichophyton sp. In an aspect, the subject demonstratesa fungal sensitization demonstrated by a positive skin test toTrichophyton sp. antigens. It is also expected that RS-norketotifen willbe effective against pulmonary infections caused by Alternaria sp.,Cladosporium sp. and Penicillium sp.

In another aspect, and built on the surprising and potent anti-moldactivity of norketotifen (Example 6), methods of treating Trichophytonasthma or Trichophyton COPD in a patient in need of such treatment andcomprising oral and/or inhaled administration to the patient in needthereof a therapeutically effective amount of racemic or isomericnorketotifen or a pharmaceutically acceptable salt thereof.

In another aspect, a method of treating airways mycosis in a patient inneed of such treatment comprises administering to the patient in needthereof a therapeutically effective amount of racemic or isomericnorketotifen or a pharmaceutically acceptable salt thereof by oraland/or inhalation routes.

Norketotifen can also be used to treat subjects in need of treatment forallergic bronchopulmonary mycosis (ABPM), which develops mainly inpatients with asthma via types I and III hypersensitivity reactions tofilamentous fungi. Aspergillus spp., especially Aspergillus fumigatus,is the major causative fungus. Aspergillus fumigatus is typically foundin the soil, however, in certain people, the immune system reacts toAspergillus fumigatus antigens in the lungs. In an aspect, the subjectexpresses fungal sensitization demonstrated by an increase in totalserum IgE and/or, the presence of IgE and IgG antibodies specific tocausative fungi such as Aspergillus fumigatus. In another aspect, thesubject demonstrates fungal sensitization demonstrated by a positiveskin test to fungal antigens.

The inventors have also unexpectedly found that norketotifen inhibitsmuscarinic M-3 receptors. Inhibitors of muscarinic M-3 receptors inhibitconstriction of bronchi and bronchioles, which may become important inthe treatment of asthma and emphysema, a form of COPD.

New drugs for COPD, such as Trelega Ellipta®, GSK, contain a steroidalanti-inflammatory (such as fluticasone) and a LABA (long-acting betareceptor agonist, such as vilanterol) and a LAMA (long-acting muscarinicantagonist), such as umeclidine, glycopyrrolate, or tiotropium.

A LABA may also be added to the combination therapy of NK for selectedpatients with severe bronchospasms. An example of a LABA to be added isvilanterol, formoterol or RR-formoterol

In another aspect, a method of treating an airways disorder in a humanpatient in need of such treatment comprises administering to the nasalpassages of the human patient in need thereof a therapeuticallyeffective amount of norketotifen, an isomer, an isomeric mixture, aprodrug or a pharmaceutically acceptable salt thereof to reduce asymptom of the airways disorder, wherein the airways disorder isnon-allergic rhinitis, vasomotor rhinitis, nonallergic rhinitis witheosinophilia, chronic rhinitis, laryngitis, sinusitis, ornasopharyngitis.

Exemplary symptoms of non-allergic rhinitis, vasomotor rhinitis,nonallergic rhinitis with eosinophilia, chronic rhinitis, sinusitis, ornasopharyngitis include inflammation of the nasal membranes with nasalcongestion, rhinorrhea, itching, sneezing, purulence, increased bodytemperature and/or nasal bleeding, and combinations thereof.

In an aspect, administration to the nasal passages comprises nasalinsufflation, nasal inhalation or administration by nose drops.

In an aspect, the therapeutically effective amount of norketotifen,isomer, prodrug or pharmaceutically acceptable salt thereof foradministration for relief of the symptoms is about 10 μg to about 1 mgper actuation, calculated as norketotifen free base.

In an aspect, a method of treating respiratory disorder in a humanpatient in need of such treatment comprises orally administering to thehuman patient in need thereof a therapeutically effective amount ofnorketotifen and administering a bronchodilating adrenergic beta-2receptor agonist such as formoterol or RR-formoterol. Formoterol orRR-formoterol, for example, can be administered by inhalation. In anaspect, the norketotifen and the bronchodilating adrenergic beta-2receptor agonist are the only drugs administered to the subject to treatthe respiratory disorder. Exemplary doses are as described above.

In another aspect, a method of treating a respiratory disorder in ahuman patient in need of such treatment comprises orally administeringto the human patient in need thereof an anti-inflammatory effectiveamount of norketotifen, wherein the norketotifen is the onlyanti-inflammatory agent administered to the subject to treat therespiratory disorder. Exemplary doses are as described above.

The embodiments disclosed herein also provide pharmaceuticalcompositions, which comprise norketotifen, formulated together with oneor more pharmaceutically acceptable carriers.

Pharmaceutical compositions for oral administration of solid dosageforms include capsules, tablets and liquid dosage forms. In solid dosageforms, the active compound may be mixed with one or morepharmaceutically acceptable excipients or carriers (such as for examplesodium citrate, dicalcium phosphate), fillers or extenders (such as forexample starch, lactose, sucrose, glucose, mannitol, silicic acid),binders (such as for example alginates, carboxymethylcellulose, gelatin,polyvinylpyrrolidone, sucrose, acacia), humectants (such as for exampleglycerol), solution retarding agents (such as for example paraffin),disintegrating agents (such as for example agar-agar, calcium carbonate,starch, alginic acid, silicates, sodium carbonate), absorptionaccelerators (such as for example quaternary ammonium compounds),wetting agents (such as for example cetyl alcohol, glycerolmonostearate), absorbents (such as for example kaolin, bentonite clay),lubricating agents (such as for example talc, calcium stearate,magnesium stearate, polyethylene glycols, sodium lauryl sulfate), and/orother excipients, such as for example buffering agents. Solid forms ofcapsules, granules, pills, and tablets can have coatings and/or shells(such as for example enteric coatings) known in the art. Thecompositions may also be designed to release the active ingredient(s) ina certain part of the gastrointestinal tract or in a controlled release,slow-release or in a delayed-release manner. The active compound(s) canalso be microencapsulated with one or more of the above-mentionedexcipients or other suitable excipients.

Liquid dosage forms for oral administration of norketotifen includepharmaceutically acceptable emulsions, solutions, suspensions, syrupsand elixirs. The liquid dosage form may also contain commonly knowndiluents (such as for example water, other solvents, solubilizingagents), emulsifiers, such as for example ethanol, isopropyl alcohol,ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,propylene glycol, butylene glycol, dimethyl formamide, oils, oleic acid,glycerol, polyethylene glycols, sorbitan fatty esters, and mixturesthereof.

Intravenous and parenteral dosage forms for administration ofnorketotifen are also contemplated herein. Such dosage forms may beparticularly useful for administration in emergency situations such asin emergency departments and urgent care centers.

The actual dosage levels of active ingredients in the pharmaceuticalcompositions disclosed herein may be varied so as to obtain the desiredtherapeutic effect. Thus, the amount of drug used varies and will dependon factors such as the administration form, the severity of the disease,the frequency of dosing, and other circumstances (such as generalhealth, body weight, age, etc.) known to the patient, the caretaker ofthe patient and/or the caring physician.

The therapeutically effective oral doses of norketotifen useful fortreating human patients with pulmonary conditions will be determined bythe caring physician and are generally 0.5 mg to 50 mg, calculated asnorketotifen free base and dosed orally as the free base or as a salt,such as for example the hydrochloride or mesylate salts or the hydrogenfumarate salt, once, twice or more times daily. In one embodiment, thetreatment is once daily dosing. The therapeutically effective dose maybe administered less than once daily, such as for example one to sixtimes weekly, wherein administration is over at least a one-week period,as determined by the patient, the caretaker of the patient and/or thecaring physician.

While oral administration is preferred, in some aspects nasalinsufflation of norketotifen may be possible.

The embodiments disclosed herein provide methods for treatment ofdisorders of the lungs in patients with norketotifen, while avoiding thesedating side effects of ketotifen and otherbenzocycloheptathiophene-related compounds, and while avoiding theadverse immune-suppressant effects of corticosteroids (see Examples 4,5) and other potent anti-inflammatory compounds. The embodiments alsoprovide treatment of pulmonary microbial disorders in human patients.Administering to the patient in need of such treatment, can consist ofeffective amounts of norketotifen free base or a pharmaceuticallyacceptable salt thereof, at a dosing frequency to be determined by theindividual human patient, the caretaker of the patient and/or the caringphysician. In one embodiment, frequency of the therapy is one or moredoses/day of norketotifen during the first week/weeks of therapy and oneor two daily doses during the following long-term maintenance therapy.The dosing under long-term maintenance therapy may be reduced to onesingle weekly dose. In one embodiment, frequency of the therapy is oneor more doses/day of norketotifen during the initial loading-dose periodand during the following maintenance dosing period. The dosing duringthe long-term maintenance therapy may be reduced to less than oncedaily, such as for example one single weekly dose.

In addition to the use of norketotifen as single-drug medication inhuman patients, embodiments disclosed herein also provide methods forco-administration of norketotifen with at least one drug of one of thefollowing classes: bronchodilating agents, antibacterial agents,antifungal agents, antiviral agents, vitamin D or vitamin D analogs,cyclooxygenase inhibitors, leukotriene antagonists, lipoxygenaseinhibitors, selective inhibitors of one or more cytokines, such as forexample kinase inhibitors and immunomodulators, such as for examplecyclosporine. The co-administration may be temporary or may bechronically used in the patient. Norketotifen and the co-administereddrug can be administered to the patient separately or can beco-formulated with norketotifen for oral, parenteral, pulmonary ordermal administration. Thus, as an example, norketotifen can beadministered orally and the co-administered drug may also beadministered orally or by inhalation. Furthermore, norketotifen and theco-administered drug may not be administered simultaneously. Thus, as anexample, norketotifen may be administered orally once daily, or onceweekly, while a co-administered adrenergic agonist may have to beadministered orally or pulmonary (by inhalation), once or more timesdaily.

When used for the treatment of pulmonary disorders, such as for exampleasthma or COPD, norketotifen can be combined with a therapeuticallyactive dose of a bronchodilating drug and the bronchodilating drug canindependently be administered by inhalation, nasal, parenteral, topical,transdermal, rectal, sublingual or oral administration. Commonbronchodilating drugs are short-acting adrenergic beta-receptoragonists, long-acting adrenergic beta-receptor agonists, anticholinergicdrugs and also methylxanthines, such as for example theophyllin. Theadrenergic beta-receptor agonist can, but will not necessarily be,selected from the group consisting of albuterol (salbutamol),terbutaline, fenoterol, formoterol, vilanterol and salmeterol and theoptically and therapeutically active isomers of adrenergic beta-receptoragonists. Examples of anticholinergic bronchodilators are tiopropium,umeclidine, glycopurrolate and ipratropium and a well-knownbronchodilating methylxanthin is theophylline. Since both bronchial andpulmonary inflammations and broncoconstriction are hallmarks of asthmaand COPD, it is advantageous that norketotifen is expressing bothanti-inflammatory and broncho-dilating activities. In cases whereadditional bronchodilatation is needed, norketotifen can be supplementedwith additional broncho-dilating drugs, such as an adrenergicbeta-receptor agonist or an additional antimuscarinic M-3 drug.

Common bronchodilators that are currently used together with inhaledsteroids are long-acting adrenergic beta-2 receptor agonists (LABAs),long-acting muscarinic M-3 antagonists (LAMAs) or combinations thereof.The two market leaders for the treatment of asthma are combinations ofthe anti-inflammatory corticosteroid fluticasone and the long-actingadrenergic beta-receptor agonist salmeterol (Advair®, Glaxo), and thecombination of the anti-inflammatory corticosteroid budesonide andlong-acting adrenergic beta-receptor agonist formoterol (Symbicort®,Astra-Zenica). LABAs and LAMAs may be combined with norketotifen.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example 1. Pulmonary Anti-Inflammatory Effects In Vivo afterOral or Parenteral Doses of Norketotifen

The migration of eosinophils to the lungs of asthma- and COPD-patientsis well known. Various pulmonary cells express adhesion molecules, towhich eosinophils bind with great avidity, leading to accumulation,degranulation and release of toxic eosinophil cationic proteins (ECPs),toxic eosinophil peroxidases (EPOs) and eosinophil-derived neurotoxins,thereby causing severe inflammatory responses of the lung tissues.

Methods

Male Sprague-Dawley rats, 400-600 g, were used in these studies.

The study described here used subcutaneous administration ofnorketotifen and ketotifen by Alzet® osmotic pumps. The rats wereadministered either RS-norketotifen hydrogen fumarate (1.0 mg/kg/day) orRS-ketotifen hydrogen fumarate (1.0 mg/kg/day) or saline. After fivedays of sc infusions of test articles and the vehicle, the animals wereinjected, i.p. with 10 μg PAF (platelet aggregating factor) in 0.25%bovine serum albumin (BSA) in saline. The subcutaneous infusions of testarticles or vehicle were continued for another twenty-four hours and theanimals were then sacrificed by intraperitoneal injections of abarbiturate. The tracheae of the euthanized animals were exposed andcannulated and aliquots (6×10 ml) of a Tyrode solution were successivelyintroduced into the lungs and aspirated by gentle compression of thethorax. The total recovery of lung fluid was usually above 80%. The cellsuspensions were concentrated by low speed centrifugation (200 g for 10min) and the resulting cell pellet was resuspended in 1 ml of a Tyrodesolution. Total cell counts were performed after dilution in Turksfluid, fixation in methanol and Leishman staining.

The study shown here used norketotifen, ketotifen, and saline (control)after continuous dosing with Alzet® Osmotic pumps. The administration ofPAF increased the pulmonary eosinophil counts to 250 percent, as shownin Table 1. Subcutaneous Alzet® dosing of ketotifen, 1 mg/kg/day for 6days, reduced the PAF-induced eosinophilia to almost non-PAF levels andthe sc dosing of norketotifen 1.0 mg/kg/day, for six days, had asupra-maximal effect, blocking the response to PAF completely andfurther reduced the eosinophil counts by 26% below the baseline(Control) level, as shown in Table 1.

TABLE 1 Inhibition of pulmonary eosinophil accumulation after continuoussubcutaneous dosing of test articles, 1 mg/kg/day for six daysPAF-induced TEST ARTICLE esosinophilia (1 mg/kg/day sc for 6 days) N (%± SEM) BSA + saline (Control) 8 100 ± 9 PAF + BSA + saline (Control) 8250 ± 4 PAF + BSA + Ketotifen HF 8 110 ± 3 PAF + BSA + Norketotifen HF10  74 ± 4 BSA = bovine serum albumin; PAF = platelet aggregating factorHF = hydrogen fumarate (salt) BSA = Bovine Serum Albumin PAF = plateletaggregating factorConclusions

Both ketotifen and norketotifen expressed anti-inflammatory effects byreduced PAF-induced eosinophilia. Norketotifen was significantly morepotent as a PAF-inhibitor than ketotifen. Thus, after subcutaneousdosing of the test articles (Table 1), norketotifen completely inhibitedall the effects of PAF and further reduced the eosinophil counts to alevel that was 26 percent below the saline control level.

In a follow-up study, it was found that the plasma concentrations ofnorketotifen in this study were very low: 4.0±0.24 ng/ml after scinfusion of RS-norketotifen for 5 days, indicating a surprisingly highpotency of norketotifen as an anti-inflammatory drug and againstpulmonary PAF-induced eosinophilia.

Most of the activity of ketotifen in this study is believed to be due tothe activity of norketotifen since ketotifen is readily metabolized tonorketotifen in rodents.

As known by those skilled in pharmacology, an oral dose of 1 mg/kg torats corresponds to a Human Equivalent Dose (HED) of 0.16 mg/kg or atotal human dose of approximately 1 mg to a human, weighing 60kilograms. Similarly, an oral dose of 3 mg/kg to rats, corresponds to atotal dose of approximately 3 mg to a human, weighing 60 kg.

Based on the results from this and similar studies and the importantroles played by eosinophils in asthma and COPD and other respiratorydiseases, it was concluded that norketotifen will be particularlyeffective as treatment for severe eosinophilic inflammatory diseases,such as eosinophilic asthma, eosinophilic COPD and non-allergic rhinitiswith eosinophilia.

Example 2. Lung/Plasma Distribution of Norketotifen (NK) in Dogs

Purpose

To determine concentrations of NK in lungs and plasma after oral dosingof NK to beagle dogs.

Methods

One group (N=3) of female Beagle dogs (8 to 10 kg/24 to 28 months) wereadministered racemic norketotifen hydrogen fumarate (RS-NK-HF) 11.46mg/kg/day for 4 consecutive days. (11.46 mg of NK-HF is equal to 8.0 mgof the free base (RS-NK-FB).

Plasma samples were collected daily on Days 2, 3 and 4. The last bloodsamples were taken four hours after dosing on Day 4. Lung and plasmaconcentrations of norketotifen were determined using a qualifiedLC-MS-MS analytical method. LLQ was <0.5 ng/ml. Immediately after bloodcollection on Day 4, all animals were euthanized with an overdose ofpentobarbital, administered intravenously, followed by exsanguination.Lung tissue samples (approximately 1 g each) were collected from eachanimal from the left and right pulmonary lobes, samples were trimmed anddried of any access blood using absorbent paper, weighed and then keptin conical tubes frozen on dry ice and stored at −80° C. pendinganalysis. Six samples from each animal (3 samples per side) wereanalyzed. The data is shown in Table 2.

TABLE 2 Day 4 Plasma and Lung Concentrations of NK in dogs at 2 hoursafter oral doses, corresponding to 8.0 mg/kg/day of NK-FB for four daysPost-dose Post-dose Lung / Lung Plasma Plasma Animal ConcentrationConcentration Ratio Number Day (ng/g) (ng/mL) in Dogs 001 4 23590 30178.4 002 4 79546 1651 48.2 003 4 61093 733 83.3 Mean ± SEM 70.0 ± 11.0Conclusions

The results from this study in three dogs demonstrated that theconcentration of norketotifen was on an average 70 times higher in thelungs of the dogs than in the plasma of the dogs.

Example 3. Lung/Plasma Distribution of Norketotifen in Rats

Purpose

Due to the surprising results from the Example 2 study in dogs, thedecision was made to repeat the Example 2 study using a differentspecies and more power.

Methods

Groups of male SPD rats (200-230 g) were administered racemicnorketotifen hydrogen Fumarate 20 mg/kg/day (=14.4 mg/kg/day of the freebase) for 10 consecutive days. Lung and plasma samples were collectedand prepared and the concentrations of RS-norketotifen were determinedusing a qualified LC-MS-MS analytical method. LLQ (Lowest Level ofQuantification) was <0.5 ng/ml. The results are provided in Table 3.

TABLE 3 Concentrations of NK free in lungs and plasma of rats during andafter once daily oral doses of NK-FB, corresponding to 14.4 mg/kg freebase for 10 days Lung Plasma Lung/Plasma Concentration ConcentrationRatio in Study Day (ng/g) (ng/mL) Rats Dose Day 4 23612 178 133 Dose Day7 25355 276 92 Last dose. Day 10 18171 229 79 Last dose + 24 hrs 890 8.3107 Mean ± SEM 103 ± 11.6Conclusion

There was a significant accumulation of norketotifen in lungs of ratswith about 100 times (103 times) higher concentration of norketotifen inlungs than in plasma. The results from this study confirm the surprisingresults from the Example 2 study.

The high dose of norketotifen used in the Example 3 study was selectedto correspond to the use of a once-a-day loading dose of norketotifenfor 10 days. The accumulation of norketotifen in the lungs is surprisingand there is no known explanation for pulmonary accumulation that can beapplied to the present results.

It was concluded that the results from the drug distribution studies indogs and rats indicate that oral administration of norketotifen mayreplace inhalation administration of steroidal drugs for patientssuffering from respiratory diseases.

Example 4: Studies on Immunosuppression

Purpose

This study was performed to evaluate possible immunosuppressant activityof RS-norketotifen.

Methods

Male BALB/c mice, 20-24 grams, 7-12 weeks, were used. The sensitizationdosing (Day 1) consisted of painting the ventral portion of thepre-shaved abdominal skin with 0.1 ml of 3.0% oxazolone in 70% ethanol.Test articles were administered orally in 1.0% methyl-cellulose,starting on Day 1 and continuing for 10 consecutive days. The challengedosing consisted of the application of 0.05 ml of 3.0% oxazolone in 70%ethanol on both sides of the outer pinna of the right ear. The thicknessof both ears of all animals was measured with a calliper before thechallenge dose and 24 hours after the administration of the challengedose (Day 10). The ear thickness of untreated mice was 0.19 to 0.20 mm.Oxazolone is not a pro-inflammatory compound and the results shown heredemonstrate immuno-suppressive effects, not anti-inflammatory activity.The results are shown in Table 4.

TABLE 4 Immunosuppression in vivo in male BalB/c mice Increase Increasein ear in ear Dose/ thick- thick- Immuno- Statistical Test day ness nesssuppression significance Article N (mg/kg) (mm) (%) (%) (P-value)Control 16 — 0.153 100.0  0  — NK 16 10.0 0.147 96.1  3.9 ≥0.25 (NS) NK16 30.0 0.140 91.5  8.5 ≥0.25 (NS) PRED  8  0.3 0.108 70.6 29.4 <0.02 PRED  8  1.0 0.084 55.0 45.0 <0.0001 PRED  8  3.0 0.076 49.7 50.3<0.0001 NK = RS-norketotifen. PRED = prednisolone. NS = no statisticalsignificance. “Ear thickness” refers to the difference in ear thicknessbetween Day 9 (before the challenge dose) and Day 10 (24 hours after thechallenge dose).Conclusions

Daily oral dosing of RS-norketotifen 10 or 30 mg/kg for 10 days to micedid not induce immuno-suppressant activity. The reference compound,prednisolone, expressed potent and dose-dependent immune suppression atdoses that were 10 times lower than the concentrations of norketotifen

Moreover, parameters examined during repeat-dose toxicology studiesrevealed no signs of immune system suppression after assessment of: (1)Hematology Indicators; (2) Clinical Chemistry Indicators; (3)Histopathology indicators; (4) Organ and Body Weight indicators.

Justification of the model: The classic oxazolone test method was usedwith minor modifications. This method has been used for over 40 years innumerous drug development projects. Oxazolone does not causeinflammation and the results shown here refer to immune-suppressiveeffects

Example 5. Anti-Inflammatory Effects of Norketotifen and Prednisolone

Purpose

To compare anti-inflammatory effects of oral doses of norketotifen (NK)and prednisolone (PRED).

Methods

The effects of NK, PRED and the vehicle (5% PEG in water) were testedorally in CD-1 female mice. Under the test protocol, 20 μl of 1.0%croton oil in acetone was applied topically to both ears of three groupsof mice, each group consisting of 6 mice. No attempt was made to removethe croton oil solution since the solvent evaporated within 30 seconds.The oral doses of NK and PRED were 10 mg/kg (10 ml/kg) bodyweight forboth compounds and were administered 60 min before the croton oilapplications. Vehicle-treated mice were dosed 10 ml/kg of water,containing 5% polyethylene glycol (PEG), which was also the solvent forthe test articles. Ear thickness was measured with an electronic caliperand mean ear thickness (N=12; right+left ears) were calculated andcompared with the thickness of ears from vehicle-treated mice (Student'st-test). As shown in Table 5, NK, but not PRED, expressed statisticallysignificant anti-inflammatory effects after oral dosing.

TABLE 5 Effects of single-dose NK and single-dose PRED on crotonoil-induced ear swelling Time after croton Average ear thickness oil,min Vehicle NK PRED 0 (predose) 0.21 ± 0.02 0.21 ± 0.02   0.22 ± 0.01 900.29 ± 0.04 0.24 ± 0.02*** 0.28 ± 0.01 120 0.28 ± 0.02 0.25 ± 0.02***0.27 ± 0.01 N = 12 ears /group. NK = norketotifen PRED = prednisoloneConclusions

NK expressed statistically significant anti-inflammatory effects whencompared with the vehicle control group. Prednisolone did not expressstatistically significant anti-inflammatory effect in this study,probably due to less anti-inflammatory potency than norketotifen.

Example 6. Antimicrobial Activity of Norketotifen

Microorganisms such as the fungi Aspergillus fumigatus, Malasseziaglobosa and Candida albicans, the molds Tricophyton rubrum andTrichophyton interdigitale and the bacteria Staphylococcus aureus,Staphylococcus intermedius, Klebsiella pneumoniae, Haemophilus influenzaand Streptococcus pneumoniae grow in human lungs, particularly inimmune-compromised patients in whom the growth of such microorganisms inthe lungs is enhanced by steroids and other immune-suppressive drugs.

Purpose

The current studies were designed to study antimicrobial activities ofnorketotifen (NK) against selected toxic microbes that are commonlyfound in the lungs of immune-compromised patients.

Methods

Samples of NK were challenged with between 1.0×10⁵ to 1.0×10⁶ cfu/ml ofmicroorganisms. The organisms were inoculated in centrifuge tubescontaining 10 mL of NK solutions and 1.0 mL samples were aliquoted fromeach centrifuge tube weekly. The logarithmic reductions of microorganismconcentrations were determined by the plate count method by diluting inDEB (D/E neutralizing Broth) from 10⁻¹ to 10⁻⁴ for fungi, mold andbacteria. Bacterial plates were poured with SCDA (Soybean Casein DigestAgar) and incubated at 32.5±2.5° C. for 3-5 days.—The water solubilityof NK about 2% (20 mg/ml). As shown in Table 6, the MICs (MinimumInhibitory Concentrations) for NK were read from the plates.

TABLE 6 Antimicrobial effects of NK-MIC-values (mg/ml for norketotifen)Fungi: MIC Mold: MIC Bacteria MIC Af Mp Ca Tr Ti Sa MRSA Si Kp Hi Sp McNK 4.0 1.0 1.0 0.5 0.5 0.5 2.0 0.25 0.5 0.25 0.5 0.25 (mg/mL) Fungi: Af= Aspergillus fumigatus. Mp = Malassezia pachydermatis. Ca = Candidaalbicans Mold: Tr = Trichophyton rubrum. Ti = Trichophytoninterdigitale. Bacteria: Sa = Staphylococcus aureus. MRSA =Methicillin-resistant S. aureus. Si = Staphylococcus intermedius. Kp =Klebsiella pnemoniae. Hi = Haemophilus influenza. Sp = Streptococcuspneumoniae, Mc = Moraxella catarrhalis. MIC refers to lethalconcentrations of NK. Those skilled in microbiology realize that staticconcentrations, such as bacteriostatic and fungistatic concentrations ofNK are lower than the lethal (MIC) concentrations.

The MIC-concentrations for norketotifen shown in Table 6 are high andmay not be reached after oral administration of norketotifen to humanpatients but said MIC concentrations will be reached after inhalation,particularly if dry powder inhalers are used. These concentrations ofnorketotifen will be reached in the lungs only after administered ofnorketotifen to the patient by use of inhalation devices, such as forexample dry powder inhalers (DPI).

Microbial infections play an important role as aeliologic factors inCOPD. Thus, it has been established that bacteria cause up to 50 percentof acute exacerbations in COPD-patients. Bacteria also play a major rolein asthma exacerbations. Chronic microbial persistence in lungs andairways is not innocuous, but cause progression of pulmonaryinflammation and airways obstruction in asthma patients.

Example 7. Effects of Norketotifen on Muscarinic M-3 Receptor Binding

Purpose

The purpose of this study was to test NK in a muscarinic M-3 receptorbinding assay.

Background

It is known to those skilled in the art that acetylcholine is binding tosmooth muscle muscarinic receptors. Binding of acetylcholine tomuscarinic M-3 receptors in the airways is causing airways constrictionand inhibition of the muscarinic receptors will cause bronchial smoothmuscle dilatation.

Methods

The current study used human M-3 (hM3) receptor and NK hydrogen fumaratewas the antagonist in the current studies. The study used NK induplicates at five dose-levels from 1.0E-08M to 1.0E-04M.

Results

As calculated from the mean values Ki (M) was calculated to be 2.2E-06Mof norketotifen free base.

Conclusions

The pulmonary distribution of NK in humans is not known. It may becomeadvantageous to co-administer norketotifen with bronchodilators, such aslong-acting antimuscarinic (LAMA) and/or long-acting adrenergicbeta-agonistic (LABA) compounds, when NK is administered to humanpatients.

Example 8: Inhibition of Cytokine Release

Purpose

The objective of this study was to assess the ability of norketotifen toinhibit cytokine release from stimulated human white blood cells.

Methods

The study was conducted in two phases. The first phase includedoptimization of the test methodology and included also dose-rangefinding studies, using buffy coats from 3 human donors, stimulated withphytohemagglutinin (PHA). The concentrations of the test article and theduration of exposure were optimized to obtain acceptable dose-responseratios. Following optimization of the test conditions, a final protocolwas issued. In the Main Study, buffy coats from 5 healthy human maledonors were stimulated with PHA, 5 μg/ml.

The inhibitory effects of three concentrations of NK and oneconcentration of ketotifen were evaluated in the Main Study. The buffycoats were resuspended in assay media and were pre-incubated for 30 minwith either vehicle/saline, ketotifen (10 μM) or norketotifen (1.0; 10or 100 μM). Following these preincubations, the white blood cellsuspensions were stimulated for 16 hours with PHA, 5 μg/ml. The cellsystem supernatants were then harvested and stored frozen.

Results

Table 7 demonstrates a lack of inhibition by ketotifen, butdose-depending inhibitory effects of NK on the in vitro release of thepro-inflammatory cytokines. TNFα, IL-4 and IL-13.

TABLE 7 Effects of norketotifen and ketotifen on PHA-induced release ofcytokines from human buffy coats. (Only pulmonary- related cytokinesshown here) Ketotifen (%) Norketotifen (%) Cytokine 10 uM 1 uM 10 uM 100uM IL-6 0.00 0.00 33.13 ¹ 88.16 ¹ TNF-α 39.98 45.57 ² 63.07 ¹ 95.68 ¹IL-4 0.00 0.00 14.32 98.27 ¹ IL-2 0.00 0.00 46.63 ¹ 93.47 ¹ IL-1β 0.000.00 16.20 57.00 ¹ IL-10 0.00 12.71 ² 24.80 ² 90.40 ¹ IFN-γ 0.00 0.0016.54 ² 71.56 ¹ IL-8 30.73 10.29 ² 34.36 ¹ 78.29 ¹ IL-13 0.00 0.00 34.49¹ 74.25 ¹ Bold values marked ¹ denote statistically significantdifference (p <0.05) when compared with vehicle. Bold values marked ²denote decrease in concentration that was not statistically significant.Conclusions

NK dose-dependently inhibited the release of cytokines from human whiteblood cells. No statistically significant inhibition of cytokine releasewas expressed by ketotifen.

Footnote

The concentration of the test article had to be high in this study sincethe test kit used a high concentration of the agonist PHA (5 μg/ml) anda long exposure time (16 hrs).

Example 9: Exemplary Oral Dosage Formulation

To make tablets, NK is blended with lactose and cellulose until auniform blend is formed. The blue lake is added and further blended.Finally, the calcium stearate is blended in, and the resulting mixtureis compressed into tablets using for example a 9/32-inch (7 mm) shallowconcave punch. Tablets of other strengths may be prepared by alteringthe ratio of active ingredient to the excipients or to the final weightof the tablet. Those skilled in the art realize that formulations canalso be administered to the patient in the form of for example acapsule, a cream, an ointment or a liquid formulation. Both norketotifensalts and norketotifen free base can be formulated as tablets.

TABLE 8 Tablet formulations Amount per Amount per Ingredient tabletbatch Norketotifen (NK)   8 mg  800 g Microcrystalline   24 mg 2400 gcellulose Lactose   56 mg 5600 g Calcium stearate  1.4 mg  140 g FD&CBlue #1 Lake 0.03 mg   3 g

Example 10: Inhalation Dosage Forms

In an aspect, a dosage form for inhalation is a nebulizer. Exemplarynebulizer devices include the Respimat®, Soft Mist™ Inhaler (BoehringerIngelheim), the AERx® Pulmonary Delivery System (Aradigm Corp.), and thePARI LC Plus® Reusable Nebulizer (Pari GmbH). An exemplary compositionfor use in a nebulizer inhaler comprises an isotonic aqueous solutioncomprising from about 0.05 μg/mL to about 10 mg/mL of norketotifen. Inone aspect, such a solution has a pH of about 3.5-6.

Alternatively, a composition comprising the active agent(s)/activeingredient(s) may be administered by inhalation using a dry powderinhaler (DPI). DPIs typically administer the active agent as afree-flowing powder that is dispersed in a subject's air-stream duringinspiration. In order to achieve a free flowing powder, the activeagent(s)/active ingredient(s) is typically formulated with a suitableexcipient such as lactose, starch, mannitol, dextrose, polylactic acid,polylactide-co-glycolide, or combinations thereof. Typically, the activeagent(s)/active ingredient(s) is micronized and combined with anexcipient to form a blend suitable for inhalation. Accordingly, in oneaspect, the active agent(s)/active ingredient(s) is in micronized form.For example, a representative composition for use in a DPI (dry powderinhaler) comprises dry lactose having a particle size between about 1 μmand about 100 μm (e.g., dry milled lactose) and micronized particles ofthe active agent. Such a dry powder formulation can be made, forexample, by combining lactose with the active agent and then dryblending the components. Alternatively, if desired, the active agent canbe formulated without an excipient. The composition is then typicallyloaded into a DPI, or into inhalation cartridges or capsules for usewith a DPI. DPIs are well known to those of ordinary skill in the art,and many such devices are commercially available, with representativedevices including Aerolizer® (Novartis), Airmax™ (IVAX), ClickHaler®(Innovata Biomed), Diskhaler® (GlaxoSmithKline), Diskus® or Accuhaler™(GlaxoSmithKline), Easyhaler® (Orion Pharma), Eclipse® (Aventis),FlowCaps® (Hovione), HandiHaler® (Boehringer Ingelheim), Pulvinal®(Chiesi), Rotahaler® (GlaxoSmithKline), SkyeHale™ or Certihaler®(SkyePharma), Synchrobreathe Inhaler (Cipla), Twisthaler®(Schering-Plough), Turbuhaler® (AstraZeneca), Ultrahaler® (Aventis), andthe like.

Alternatively, the composition comprising the active agent may beadministered by inhalation using a metered-dose inhaler (MDI). Such MDIstypically discharge a measured amount of the active agent usingcompressed propellant gas. Metered-dose formulations thus typicallycomprise a solution or suspension of the active agent in a liquefiedpropellant, such as a chlorofluorocarbon such as CCl₃F or ahydrofluoroalkane (HFA) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), although HFAs aregenerally preferred due to concerns about chlorofluorocarbons affectingthe ozone layer. Additional optional components of HFA formulationsinclude co-solvents, such as ethanol or pentane, and surfactants, suchas sorbitan trioleate, oleic acid, lecithin, and glycerin. Arepresentative composition for use in an MDI comprises from about 0.01-5wt % of active agent; from about 0-20 wt % ethanol; and from about 0-5wt % surfactant; with the remainder being an HFA propellant. Suchcompositions are typically prepared by adding a chilled or pressurizedhydrofluoroalkane to a suitable container containing the active agent,ethanol (if present) and the surfactant (if present). To prepare asuspension, the active agent is micronized and then combined with thepropellant. The formulation is then loaded into an aerosol canister,which forms a portion of the MDI. MDIs are well known to those ofordinary skill in the art, and many such devices are commerciallyavailable, with representative devices including AeroBid® Inhaler System(Forest Pharmaceuticals), Atrovent® Inhalation Aerosol (BoehringerIngelheim), and the like. Alternatively, a suspension formulation can beprepared by spray drying a coating of surfactant on micronized particlesof the active agent.

Example 11: Intranasal Dosage Forms

Intranasal dosage forms can be formulated in an aerosol form, spray,mist or in the form of drops. Intranasal compositions can include amucoadhesive agent, a solubilizer, a preservative, a flavoring agent, avehicle, and combinations thereof.

Examples of mucoadhesive agent include, but are not limited topolyacrylic polymers like carbopols, polycarbophil,carboxymethylcellulose or its pharmaceutically acceptable salt,microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose (i.e., hypromellose),methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatinalone or in any combination thereof. Nasal compositions can containabout 0.05 to about 5% w/v of a mucoadhesive agent.

Examples of solubilizers (or crystal growth inhibitors) include, but arenot limited to d-alpha tocopheryl polyethylene glycol 1000 succinate(Vitamin E TPGS), macrogol (15)-hydroxystearate (Solutol HS 15),polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic, such aspoloxamer 188), PEO-PLLA diblock copolymer, PEG-PLGA-PEG triblock,copolymer, cyclodextrins, hydroxypropyl betadex, polyoxyethylene castoroil derivatives, povidone, sulfobutylether-b-cyclodextrin, tricaprylin,triolein, glyceryl monostearate, sorbitan esters (sorbitan fatty acidesters), polyoxyethylene fatty acid esters, polysorbate 80, polysorbate20 or macrogol-15-hydroxysterate. Nasal compositions can contain fromabout 0.2 to about 10.0% w/v of a solubilizer.

Examples of preservatives include benzalkonium chloride, sodiumbenzoate, methyl, ethyl, propyl or butyl paraben, benzyl alcohol,phenylethyl alcohol, benzethonium chloride, chlorobutanol, potassiumsorbate or combination thereof. Nasal compositions can contain fromabout 0.01 to about 1% w/v of a preservative. Liquid compositionscontaining norketotifen may not need an added preservative since theantimicrobial activity of the norketotifen molecule can make theformulations self-preserving, which is advantageous since preservatives,such as benzalkonium chloride are toxic entities.

Exemplary flavoring agents include flavor anise, flavor apple, flavorapricot, flavor banana, flavor buttermint, flavor citrus, flavor orange,flavor menthol mint, flavor mint, flavor peppermint, flavor spearmint,alone or in any combinations thereof. Nasal compositions disclosed maycontain from about 0.01% w/v to about 0.5% w/v of a flavoring agent.

Examples of vehicles include, but are not limited to, saline, water,dextrose or combinations thereof. The pH of compositions describedherein may be about 3.0 to about 7.4 and all values in between.

As used herein, the terms “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to norketotifen salts,which have been prepared from pharmaceutically acceptable non-toxicacids. Exemplary pharmaceutically acceptable acid as for the compound ofthe present invention include acetic, benzenesulfonic (besylate),benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrogen fumaric, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric,tartaric, and the like. The hydrochloride salt and the hydrogen fumaratesalt are particularly preferred.

The term “antimicrobial” as used herein refers to antibacterial,antifungal and anti-mold activities or effects.

The term “patient” as used herein refers to human patients and caninepatients.

The use of the terms “a” and “an” and “the” and similar referents(especially in the context of the following claims) are to be construedto cover both the singular and the plural, unless otherwise indicatedherein or clearly contradicted by context. The terms first, second etc.as used herein are not meant to denote any particular ordering, butsimply for convenience to denote a plurality of, for example, layers.The terms “comprising”, “having”, “including”, and “containing” are tobe construed as open-ended terms (i.e., meaning “including, but notlimited to”) unless otherwise noted.

As used herein, when referring to dosage amount, the term “about”includes amounts to ±10% of the recited value.

As used herein, the term “chronic administration” is defined as three ormore consecutive days of administration. Acute administration ofnorketotifen refers to a single administration of the drug.

Recitation of ranges of values are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. The endpoints of all ranges are includedwithin the range and independently combinable. All methods describedherein can be performed in a suitable order unless otherwise indicatedherein or otherwise clearly contradicted by context. The use of any andall examples, or exemplary language (e.g., “such as”), is intendedmerely to better illustrate the invention and does not pose a limitationon the scope of the invention unless otherwise claimed. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the invention as used herein.

While the invention has been described with reference to a preferredembodiment, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing fromessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

The invention claimed is:
 1. A method of treating a human patient inneed of treatment for asthma or chronic obstructive pulmonary disorder(COPD), the method comprising administering orally or by oral inhalationan anti-inflammatory corticosteroid medication; discontinuing thecorticosteroid medication; and administering orally or by oralinhalation to the human patient a therapeutically effective amount ofthe anti-inflammatory compound norketotifen, an isomer, an isomericmixture, a prodrug, or a pharmaceutically acceptable salt thereof,wherein the norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof reduces the immune-suppressioncaused by the anti-inflammatory corticosteroid medication, wherein theprodrug is

wherein R is hydroxy-C₂-C₆ alkyl or carboxy-C₁-C₆alkoxy-C₁-C₆alkyl,wherein the human patient is a critically sick patient and wherein thenorketotifen, isomer, isomeric mixture, prodrug, or pharmaceuticallyacceptable salt thereof provides improved breathing and life-savingtherapy to the human patient; wherein the norketotifen, isomer, isomericmixture, prodrug, or pharmaceutically acceptable salt thereof prolongslife compared to no treatment or treatment with the corticosteroid; or acombination thereof.
 2. The method of claim 1, wherein thetherapeutically effective amount of norketotifen, isomer, isomericmixture, prodrug, or pharmaceutically acceptable salt thereof is 0.5 to50 mg, calculated as base and administered one or more times per day tothe patient in need thereof.
 3. A method of treating a human patient inneed of treatment for an acute exacerbation of asthma or an acuteexacerbation of chronic obstructive pulmonary disorder (COPD), themethod comprising orally or by oral inhalation administering to thehuman patient in need thereof a therapeutically effective amount ofnorketotifen, an isomer, an isomeric mixture, a prodrug, or apharmaceutically acceptable salt thereof; wherein the therapeuticallyeffective amount of norketotifen, an isomer, an isomeric mixture, aprodrug, or a pharmaceutically acceptable salt thereof provides aconcentration of norketotifen in the lungs of the patient that isgreater than or equal to the minimum inhibitory concentration (MIC) ofnorketotifen for Haemophilus influenza, Streptococcus pneumoniae,Moraxella catarrhalis, Staphylococcus aureus, Staphylococcusintermedius, Klebsiella pneumoniae, a Trichophyton sp., or a combinationthereof, wherein the prodrug is

wherein R is hydroxy-C₂-C₆ alkyl or carboxy-C₁-C₆alkoxy-C₁-C₆alkyl. 4.The method of claim 3, wherein the MIC for Haemophilus influenza isabout 0.25 mg/ml, the MIC for Streptococcus pneumoniae is 0.5 mg/ml, andthe MIC for Moraxella catarrhalis is 0.25 mg/ml.
 5. The method of claim3, wherein the norketotifen, isomer, isomeric mixture, prodrug, orpharmaceutically acceptable salt thereof relieves one or more symptomsof asthma or COPD selected from phlegm, stabbing chest pain, shortnessof breath, difficult breathing, wheezing, yellow or green colored mucus,fever, chills, throat pain, sinus drainage and congestion.
 6. The methodof claim 3, wherein the therapeutically effective amount ofnorketotifen, isomer, isomeric mixture, prodrug, or pharmaceuticallyacceptable salt thereof is 0.5 to 50 mg, calculated as base andadministered one or more times per day to the patient in need thereof.7. A method of treating a patient suffering from chronic obstructivepulmonary disorder (COPD) or asthma, comprising orally or by oralinhalation administering to the human patient a therapeuticallyeffective amount of norketotifen, an isomer, an isomeric mixture, aprodrug, or a pharmaceutically acceptable salt thereof, while avoidinginflicting said patients with adverse corticosteroidal side effects,wherein the prodrug is

wherein R is hydroxy-C₂-C₆ alkyl or carboxy-C₁-C₆alkoxy-C₁-C₆alkyl,wherein the human patient is a critically sick patient and wherein thenorketotifen, isomer, isomeric mixture, prodrug, or pharmaceuticallyacceptable salt thereof provides improved breathing and life-savingtherapy to the human patient; wherein the norketotifen, isomer, isomericmixture, prodrug, or pharmaceutically acceptable salt thereof prolongslife compared to no treatment or treatment with the corticosteroid; or acombination thereof.
 8. A method of treating human patient in need oftreatment for an acute exacerbation of chronic obstructive pulmonarydisorder (COPD), the method comprising orally or by oral inhalationadministering to the human patient in need thereof a therapeuticallyeffective amount of norketotifen, an isomer, a prodrug, or apharmaceutically acceptable salt thereof, wherein the therapeuticallyeffective amount of norketotifen, isomer, prodrug, or pharmaceuticallyacceptable salt thereof provides a concentration of norketotifen in thelungs that is greater than or equal to the minimum inhibitoryconcentration (MIC) for Haemophilus influenza, Streptococcus pneumoniae,Moraxella catarrhalis, or a combination thereof, wherein the prodrug is

wherein R is hydroxy-C₂-C₆ alkyl or carboxy-C₁-C₆alkoxy-C₁-C₆alkyl. 9.The method of claim 8, wherein the MIC for Haemophilus influenza is 4.0mg/ml, the MIC for Streptococcus pneumoniae is 0.5 mg/ml, and the MICfor Moraxella catarrhalis is 0.25 mg/ml.
 10. The method of claim 8,wherein the norketotifen, isomer, prodrug, or pharmaceuticallyacceptable salt thereof relieves a symptom selected from phlegm,stabbing chest pain, shortness of breath, difficult breathing, wheezing,yellow or green colored mucus, fever, chills, throat pain, sinusdrainage or congestion, headache, and combinations thereof.
 11. Themethod of claim 8, further comprising diagnosing a respiratoryinfection.
 12. The method of claim 11, wherein the infection isdiagnosed by medical imaging, spirometry, pulse oximetry, mucus culture,throat swab, complete blood count, blood culture, or a combination ofthe foregoing.